MODE OF ACTION OF TRYPANOCIDAL CATIONIC DRUGS

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The objectives of this proposal are to study, in detail, the mechanism or mechanisms by which gentian violet and other cationic drugs exert their trypanocidal action, and the metabolism of these compounds by Trypanosona cruzi and mammalian systems. The goal of these studies will be the elucidation of differences between host and parasite that could be exploited for chemoprophylactic purposes. The effect of cationic drugs on cellular membranes will be one area of concentration since an uncoupling effect of gentian violet on mitochondrial oxicative phosphorylation has recently been found. The second portion of the proposal will consist in exploring the chemoprophylactic potential of the photodynamic action of gentian violet recently demonstrated. Finally, the third portion of the studies will concentrate on the metabolism of gentian violet in Trypanosoma cruzi and mammalian systems. There studies will clarify the role of metabolic transformations in parasite resistance to chemoprophylaxis and the importance of gentian violet metabolites in its toxicity and carcinogenic potential.